Long-Acting Antipsychotics Tied to Superior Outcomes

Pam Harrison

June 14, 2017

"Real-world" use of clozapine (multiple brands) and long-acting injectable antipsychotics is associated with the lowest risk for rehospitalization and treatment failure in newly diagnosed and longer-term patients with schizophrenia, a population-based cohort study suggests.

"It has been estimated that only about 5% to 10% of the most compliant patients with no comorbidities are included in randomized controlled trials (RCTs), so it's rather meaningless to study the putative beneficial outcomes related to long-acting injections (LAIs) in RCTs, because poorly compliant patients who would benefit from LAIs are excluded from these trials," Jari Tiihonen, MD, PhD, professor of clinical neuroscience, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

"[Because] our results suggest that there are substantial differences between specific antipsychotic agents and between routes of administration, I think it's important for physicians to realize that there are large differences in the real-world effectiveness of different antipsychotics, and they need to keep these differences in mind when prescribing drugs for patients with schizophrenia," he added.

The study was published online June 7 in JAMA Psychiatry.

Real-World Study

The investigators used nationwide register-based data that included 29,823 patients living in Sweden who were diagnosed with schizophrenia between July, 2006, and December, 2013. This group was designated as the prevalent cohort.

The researchers also derived an incident cohort that included patients newly diagnosed with schizophrenia. To overcome residual confounding associated with individual patients, the researchers also conducted a within-individual analysis, in which each person served as his or her own control.

During a mean follow-up of 5.7 years in the prevalent cohort, 43.7% of patients required rehospitalization for psychiatric reasons, and 71.7% of the cohort experienced treatment failure. Treatment failure was defined as a patient's requiring psychiatric rehospitalization, discontinuance of therapy, switching to a different antipsychotic, or death. A second definition for treatment failure excluded any switch to another medication.

The lowest risk for rehospitalization was observed for once-monthly, long-acting, injectable paliperidone (Invega Sustenna, Janssen), the investigators report. This therapy was 49% less likely to be associated with the need for psychiatric rehospitalization compared with no antipsychotic use (hazard ratio [HR], 0.51).

Patients who received clozapine were 47% less likely to require psychiatric rehospitalization compared to patients with no antipsychotic use (HR, 0.53).

Rehospitalization risks were identical with long-acting injectable perphenazine (Trilafon, Schering) (HR, 0.58) and long-acting olanzapine (Zyprexa, Lilly) (HR, 0.58) compared with no antipsychotic use.

The researchers found the highest risk for rehospitalization was with oral flupentixol (multiple brands) and quetiapine (Seroquel, AstraZeneca). The most frequently used antipsychotic was oral olanzapine.

Compared with oral olanzapine, patients treated with clozapine were 16% less likely to require rehospitalization. Those treated with long-acting injectable zuclopenthixol (multiple brands) were 17% less likely to be rehospitalized (P < .001).

In contrast, those treated with quetiapine were 43% more likely to require rehospitalization. Those treated with oral flupentixol (multiple brands) were 46% more likely to require psychiatric rehospitalization compared with patients treated with oral olanzapine. Patients treated with oral haloperidol (Haldol, Ortho-McNeil) were 28% more likely to require rehospitalization compared with patients who received oral olanzapine (P < .001).

"In within-individual analysis, the risk of rehospitalization was 22% lower during use of long-acting injectable antipsychotic medications compared with use of corresponding oral formulations (P < .001)," the researchers write.

The risk for psychiatric rehospitalization was 32% lower among patients in the newly diagnosed group who were treated with a long-acting injectable antipsychotic compared with those treated with the equivalent oral formulation.

Treatment Failure

The investigators also found that patients treated with clozapine were at lowest risk for treatment failure, at 42%, compared with patients treated with oral olanzapine (HR, 0.58).

The second lowest risk for treatment failure was seen for all long-acting injectable antipsychotics compared with oral olanzapine.

The greatest likelihood for treatment failure was associated with use of levomepromazine (multiple brands); patients treated with levomepromazine were 15% more likely to experience treatment failure than those treated with oral olanzapine.

"When a switch to another antipsychotic medication was not included in the definition of treatment failure, clozapine was still associated with the best outcome...compared with oral olanzapine," the investigators write.

The team also directly compared long-acting injectable antipsychotics to the oral formulation of the same second-generation antipsychotic in patients experiencing a first episode of schizophrenia.

In this incident, newly diagnosed cohort, they found that the risk for relapse was 85% lower with the long-acting injectable formulation compared to its oral counterpart.

"[This] suggests that the greatest benefit of long-acting injectable antipsychotic medications is achieved among newly diagnosed patients," the authors note.

It is "remarkable," they add, that the risk for psychiatric rehospitalization was 40% to 70% higher among patients who received quetiapine as monotherapy compared with those treated with clozapine, oral olanzapine, or the most frequently used long-acting injectable antipsychotics.

"Quetiapine has been the most commonly used antipsychotic in many countries," they note. "Our results [suggest] that quetiapine should not be used routinely as monotherapy for patients with schizophrenia without specific reasons," they add.

The researchers also suggest that the favorable findings seen with the long-acting injectables were largely due to better adherence with this type of formulation.

Patient Preference

Commenting on the findings for Medscape Medical News, Scott Hamilton, MD, OSF Behavioral Health, Normal, Illinois, noted that he himself does not employ long-acting injectable formulations as much as would be ideal and that that is likely true throughout the United States in general.

"Sometimes patients are unwilling to accept them — I've had that happen several times when I've suggesting a long-acting injectable formation ― so sometimes it is a patient issue," Dr Hamilton added.

The study's finding that outcomes with long-acting injectable antipsychotics are superior to those with oral formulations, even oral formulations of the same antipsychotic, is not that new and that similar results been reported before, he said.

However, Dr Hamilton noted that what was novel about the study was how outcomes for newly diagnosed patients who received long-acting injectable antipsychotics were better than outcomes for newly diagnosed patients who received oral agents.

"New-onset patients are more likely to fail than those with more established schizophrenia, and they are more likely to be noncompliant, so that's probably the primary population we should go for," Dr Hamilton said.

"And if we can keep these new-onset patients from experiencing repeated episodes of illness, than their long-term course is likely going to be better, and they will likely have fewer side effects and less morbidity from the illness.

"So the take-home I get from this study is that we really ought to be considering long-acting injectables earlier on in the course of the patient's illness," he added.

The study was funded by Janssen-Cilag. The authors have disclosed various relationships with industry, which are listed in the original article. Dr Hamilton is on the speaker's bureaus for Sunovion and Allergan, both of which make oral antipsychotics.

JAMA Psychiatry. Published online June 7, 2017. Abstract

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